Phytosterols are plant sterols structurally similar to cholesterol that have been known for many years to reduce cholesterol absorption and serum cholesterol levels while not being absorbed themselves. Lowering of circulating cholesterol and low density lipoprotein cholesterol is an important part of a strategy to prevent and treat cardiovascular disease and especially coronary heart disease. Cholesterol absorption is a critical component of whole body cholesterol metabolism. Cholesterol derived from the diet and also from endogenous biliary secretion enters the intestine, and approximately 50% of the mixed intestinal load is absorbed, Bosner, M. S., Ostlund, R. E., Jr., Osofisan, O., Grosklos, J., Fritschle, C., Lange, L. G. 1993. The failure to absorb cholesterol quantitatively is therefore a key mechanism for the elimination of cholesterol from the body.
Drugs commonly used to treat high cholesterol levels have little or no effect on cholesterol absorption. For example, the potent new hydroxymethylglutaryl coenzyme A reductase inhibitors have a primary action to reduce cholesterol synthesis rather than increase cholesterol elimination. Bile acid sequestrants such as the ion-exchange resin cholestyramine act within the intestine but do not bind cholesterol and may actually increase cholesterol absorption when given chronically. McNamara, D. J., N. O. Davidson, P. Samuel, and E. H. Ahrens, Jr. 1980, Cholesterol absorption in man:effect of administration of clofibrate and/or cholestyramine. J. Lipid Res. 21:1058-1064. Although orally-administered neomycin reduces cholesterol absorption effectively, it is toxic and has the disadvantage of requiring chronic administration of a potent antibiotic, Samuel, P. 1979. Treatment of hypercholesterolemia with neomycin--A time for reappraisal. N. Engl. J. Med. 301:595-597. The drug Cytellin.RTM., an aqueous suspension of mixed phytosterols, was produced by Eli Lilly Co. for treatment of elevated cholesterol, but it has not been sold since 1985. As seen, it is apparent that new inhibitors of cholesterol absorption would complement currently-available treatment for high serum cholesterol.
Since phytosterols are natural products which are non-toxic and inexpensive byproducts of food processing, they may be important in the treatment of individuals with mildly-increased serum cholesterol, or for the general population in food products or dietary supplements. The use of phytosterols could reduce the need for systemically-absorbed drugs.
Despite their potential attractiveness, the usefulness of phytosterols has been limited by small and erratic effectiveness and a large dosage requirement. For example, doses of 5-18 g sitosterol/day reduced serum cholesterol by 16-20%. Farquhar, J. W. and M. Sokolow, 1958. A dose-response study showed that 3-9 g/day of powdered sitosterol was needed to decrease serum cholesterol levels by 12%. Lees, A. M., H. Y. I. Mok, R. S. Lees, M. A. McCluskey, and S. M. Grundy. 1977. Plant sterols as cholesterol-lowering agents:clinical trials in patients with hypercholesterolemia and studies of sterol balance, Atherosclerosis 28:325-338. To reduce the amount needed, recent experiments have used sitostanol instead of sitosterol because it appears to be more potent than other phytosterols and is non-absorbable, Sugano, J., H. Morioka, and I. Ikeda. (1977) A comparison of hypocholesterolemic activity of .beta.-sitosterol and .beta.-sitostanol in rats. J. Nutr. 107:2011-2019. In subjects with severe hypercholesterolemia sitostanol at 1.5 g/day reduced serum cholesterol by 15%, Heinemann, T., O. Leiss, and K. von Bergmann (1986) Effect of low-dose sitostanol on serum cholesterol in patients with hypercholesterolemia. Atherosclerosis 61:219-223. However, sitostanol at 3 g/day had no effect in subjects with moderate hypercholesterolemia. Denke, M. A. (1995), Lack of efficacy of low-dose sitostanol therapy as an adjunct to a cholesterol-lowering diet in men with moderate hypercholesterolemia. Am. J. Clin. Nutr. 61:392-396.
Several investigators have proposed ways to increase the solubility or bioavailability of phytosterols in order to make them more useful. Based on studies in rats and the finding that phytosterol esters are much more soluble in oil than the free sterols, it has been proposed to use phytosterol esters in oil to lower cholesterol absorption, Mattson, F. H., R. A. Volpenhein, and B. A. Erickson (1977), Effect of plant sterol esters on the absorption of dietary cholesterol. J. Nutr. 107:1139-1146. U.S. Pat. No. 5,502,045 describes the use of sitostanol ester in oil for the treatment of hypercholesterolemia in humans. It was found that 2.8 g sitostanol/day given as sitostanol ester in margarine reduced LDL cholesterol by 16%. Miettinen, T. A., P. Puska, H. Gylling, H. Vanhanen, and E. Vartiainen (1995), Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N. EnglandJ. Med. 333:1308-1312. However, the use of sitostanol ester dissolved in dietary fat has the disadvantage of requiring the administration of 23-50 g/day of dietary fat and of being 21% less effective at reducing cholesterol absorption in humans compared to the unesterified sterol. Mattson, F. H., S. M. Grundy, and J. R. Crouse, (1982), Optimizing the effect of plant sterols on cholesterol absorption in man. Am. J. Clin. Nutr. 35:697-700.
Additional workers have investigated ways to improve the usefulness of unesterified phytosterols. In International patent Publication WO 95/00158 a complex of sitosterol and the unabsorbable dietary fiber pectin reduced serum cholesterol by 16.4% when given to hypercholesterolemic humans in a dose of 2.1 g/day. However, no measurements of an effect on cholesterol absorption were made, and the complex was only about 50% soluble even at strongly alkaline pH, suggesting that the bioavailability of the sitosterol component was limited.
U.S. Pat. No. 5,244,887 describes the use of stanols including sitostanol in food additives to reduce cholesterol absorption. In U.S. Pat. No. 5,244,887, for preparation of the additives, sitostanol is dissolved with an edible solubilizing agent such as triglyceride, an antioxidant such as tocopherol, and a dispersant such as lecithin, polysorbate 80, or sodium lauryl sulfate. However, no data were given to guide one in the selection of the most effective components and their amounts or specific methods of preparation. Effectiveness in reducing cholesterol absorption was also not determined. The preferred embodiment consisted of 25% by weight stanols in vegetable oil, but the solubility of sterols in oil is only 2%.
U.S. Pat. No. 5,118,671 describes the production of sitosterol-lecithin complexes for pharmaceutical use but does not consider oral use for cholesterol lowering.
Cholesterol is absorbed from an intestinal micellar phase containing bile salts and phospholipids which is in equilibrium with an oil phase inside the intestine. Delivery of phytosterol as a solid powder or aqueous suspension is not preferred because of the limited rate and extent of solubility in intestinal liquid phases. Esterification of the phytosterol with delivery through the oil phase of foods is an alternative route but has the disadvantage of use of edible oils as the carrier.
Accordingly, it is an object of the present invention to provide a delivery system for plant sterols, particularly sitostanol, which avoids an oil phase and which provides bioavailable sitostanol at a level which reduces cholesterol absorption as much as 37%, while at the same time using an excellent taste emulsifier in as low amounts as possible.
Another objective of the present invention is to provide a water soluble composition which provides the sitostanol, not dissolved in fat, but rather combined with a preferred emulsifier (Sodium Stearoyl 2-lactylate)(SSL) in an aqueous vesicular complex which can enter directly into the intestinal micellar phase and is therefore highly bioavailable.
Another objective of the present invention is to provide a composition of preferred enhanced solubility that contains a plant sterol, preferably sitostanol mixed with an emulsifier even better than phospholipids, namely SSL, which has water solubility in excess of 90%.
Another objective of the present invention is to provide a method for reducing cholesterol absorption from food products containing cholesterol by mixing finely divided water soluble powder of an aqueous homogeneous micellar mix of sitostanol and SSL with a food product which is to be ingested.
A yet further objective of the present invention is to provide a method of manufacturing a dry, finely divided water soluble powder which contains a plant sterol, preferably sitostanol, and lecithin, which is highly water soluble, so that when in contact with an aqueous system it will provide an aqueous vesicular complex which can enter directly into the intestinal micellar phase to inhibit cholesterol absorption.
The method and manner of achieving each of the above objectives, as well as others, will become apparent from the detailed description of the invention which follows hereinafter.